This invention generally pertains to heterocyclic carbon compounds having drug and bio-affecting properties and to their preparation and use. In particular, the invention is concerned with disubstituted cycloalkanyl and cycloalkenyl derivatives wherein one substituent moiety is a 5-substituted indol-3-yl group and the other moiety is an aryl or a heteroaryl, e.g. pyridinyl, ring. These compounds possess a unique serotonergic profile that renders them, inter alia, useful in treatment of vascular headaches such as migraine or cluster type.
Dowie, et al. disclosed a series of 3-alkylamino-indole derivatives as being potentially useful for the treatment of migraine in a published patent application, GB 2,124,210. One member of this series of compounds was specifically claimed in a later patent application of Oxford, GB 2,162,522, published Feb. 5, 1986. This particular compound is known in the literature as sumatriptan(i). ##STR2##
A number of sumatriptan derivatives comprising variations in the 5-indolyl-substituent have been disclosed, e.g. WO 9311106 by Macor; as well as disclosures of variations in the 3-indolyl-alkylamino substituent, e.g. WO 9213856 by Nowakowski.
Structural variations involving replacement of the dialkylamino moiety by incorporation of a piperazinyl ring system to give compounds of formula (ii) have been disclosed. ##STR3##
Compounds of formula (ii) are known wherein Ar is a pyridine ring (U.S. Pat. No. 4,954,502 to Smith, et al.); an optimally substituted phenyl ring (Canadian patent application 2,059,708 by Bottcher, et all.); and a pyrimidinyl system (EP 0548813A by Smith, et al.).
Related hydropyridine compounds of formula (iii) have also ##STR4## been synthesized and disclosed as antipsychotics (FR 2458550); antidementia agents (WO 9215303 by Perrigaard, et al.) and agents for treating substance abuse (WO 9215302 by Perrigaard, et al.).
More closely related, at least in terms of molecular structure, are compounds of formula (iv) which have been ##STR5## disclosed as dopaminergic agents for treating psychosis (U.S. Pat. No. 5,124,332 to Wise, et al. and WO 9310092 by Caprathe, et al.); and cerebral ischemia (EPO-A 0560669 by Mattson, et al.).
None of the foregoing references, either singly or in combination, teach or suggest the particular combination of structural variants comprising the novel compounds of the present invention nor their use as serotonergic agents with particular utility in treating migraine headache.
Migraine is a member of a broader class of headache that also comprises cluster headaches and other headaches believed to have a vascular implication in their etiology. These headaches are often classified as vascular headaches. For a current summary of headache and its treatment see: Chapter 13: "Drugs Used to Treat Migraine and Other Headaches" in Drug Evaluations, 6th Edn., 1986, pages 239-253 American Medical Association, W.B. Saunders Co., Philadelphia, Pa.
Frequent irregularly-occurring episodes of headache afflict a large number of people but are usually acute in nature and of short duration. Relief of this type of headache is typically provided by mild analgesics such as aspirin or acetaminophen. Such headaches are quite common and, while painful and perhaps annoying, are seldom incapacitating and debilitating. Chronic recurrent headaches of the vascular category, however, usually lead to patient consultation with a physician due to pain severity which is often incapacitating.
Although there is no universally accepted classification system for headache, vascular headache, for the purposes of the present invention, refers mainly to migraine and cluster headaches. Migraine includes the common or classical type as well as migraine variants which would be familiar to one skilled in the art. Other subtypes such as toxic vascular and hypertensive headaches, chronic paroxysmal hemicrania, as well as some muscle-contraction and combined or mixed vascular-muscle headaches may also fall into a vascular-related headache category and be treatable by the present invention. It is appreciated by one skilled in the art that no single therapy is effective in all patients diagnosed with the same subtype of headache, thereby raising further uncertainties about headache classification.
The present invention relates to novel indolyl-cycloalkanyl and cycloalkenyl derivatives of arylalkylamines, their therapeutic use as serotonergic agents, particularly in headache therapy and their pharmaceutical compositions.